PROJECT SUMMARY/ABSTRACT There are few treatments for persistent impulsive aggression in individuals with severe neuropsychiatric disorders, and existing treatments are of limited efficacy yet confer the potential for significant side effects. Aggression contributes to repeat institutionalization and significant costs to healthcare and criminal justice systems. As a neuroscientist and board-certified psychiatrist, this mentored patient-oriented research career development award (K23) will provide training to support Dr. Lewis's goal of becoming an independent translational investigator focused on the development of novel therapeutic approaches informed by the neural circuitry regulating impulsive aggression. To accomplish his career and research goals, Dr. Lewis will receive training in translational neuroscience by acquiring new skills to manipulate neural circuitry in mice and humans, identify effects on behaviors related to impulsive aggression, and rigorously analyze resulting data. Training will be guided by a team of mentors and contributors who are leaders in the basic and translational science of neural circuits underlying behavior relevant to neuropsychiatric disorders as well as in statistical analysis. The research plan is supplemented by coursework at Yale in translational neuroscience and statistical modeling, as well as participation in relevant seminars and national scientific meetings. The proposed experiments build upon preliminary data in mouse models demonstrating that activation of ?7 nicotinic receptors in the dentate gyrus (DG) reduces aggressive behavior, while reduction of ?7 receptors increases aggressive behavior. Because ?7 receptors are highly enriched on local inhibitory interneurons of the DG and their activation enhances DG and hippocampal inhibition, the hypothesis will be tested that hippocampal excitatory-inhibitory (E/I) balance governs the expression of aggressive behavior in mice and humans. In Aim 1, activity of excitatory or inhibitory neurons in the mouse DG will be recorded using fiber photometry and manipulated using optogenetics to determine how DG E/I balance influences aggression onset in real time during resident- intruder tests. In Aim 2, this circuit mechanism will be translated to human subjects with schizophrenia using a pharmacological probe. The ?7 partial agonist GTS-21 will be orally administered to enhance hippocampal inhibition, and an Emotional Go/NoGo Task used to determine effects on impulsive responding to negative and neutral valence stimuli. This behavioral task is mediated by prefrontal-temporolimbic circuitry, including the hippocampus, and performance correlates with a history of impulsive aggression in schizophrenia patients. These focused experiments take an innovative translational approach in mice and humans to understand how hippocampal activity influences behavioral measures related to impulsive aggression in neuropsychiatric disorders. Training in contemporary techniques of translational neuroscience, deliberate integration of animal and human paradigms, and data analysis will serve as a critical foundation to support Dr. Lewis's independent translational research career focused on identifying novel therapeutic options for impulsive aggression.